Functions for novel IL-15-responsive macrophages in the uterus during pregnancy

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PROJECT SUMMARY The goal of my five-year Mentored Clinical Scientist Research Career Development Award is for me to develop into a productive, independent academic investigator in the field of reproductive immunology. I completed an MD and a PhD in the field of cellular immunology, and I now seek to apply my interest in dysregulated immunity to the public health threat of adverse fetal and maternal outcomes of pregnancy. I am now a physician-scientist in Neonatology and Assistant Professor on faculty at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). My primary mentor for this award, Dr. Edward M. Behrens, is a physician-scientist and Chief of the Division of Rheumatology with a longstanding track record of scientific innovation and providing exceptional mentoring to trainees at all levels. As an internationally-recognized expert in innate immunity and inflammatory disorders, Dr. Behrens’s work complements my own. We are thus poised for productivity. My scientific advisory committee includes scientists and physician-scientists with collective expertise in all aspects of the proposed work, from placental biology to next-generation sequencing. I am also extremely fortunate to have the unreserved support of CHOP and Penn, whose combined resources are unmatched. The goal of this one-year supplement is to provide funding for additional personnel who will promote my to return to full research productivity after facing a critical life event soon after opening my laboratory. Given the extent of my caregiving responsibilities for my two young children during this period, I have already received an extension of the tenure clock from my supportive institution. This supplemental research support from the NIH will be instrumental in timely completion of the original aims of my K08. Scientifically, the proposal focuses on roles for novel macrophages that I discovered under the guidance of Dr. Behrens, called CD122+Macs, in normal and threatened pregnancy. Enriched in the uterus in mice and humans, CD122+Macs express high levels of CD122, the hallmark of responsiveness to interleukin-15 (IL-15). These novel Macs signal and function when exposed to IL-15, surprising because killer lymphocytes like natural killer (NK) cells, not Macs, are the classical targets of IL-15. Disrupted homeostasis of IL-15 is associated with numerous adverse outcomes of pregnancy, including preeclampsia and abnormal feto-placental growth but through unknown mechanisms. Based on prior literature and my preliminary data, my central hypothesis is: IL- 15 exerts its influence over outcomes of pregnancy not only by maintaining NK cells but also by modulating the inflammatory properties of novel CD122+Macs. The aims of this proposal will establish: 1) Mechanisms by which CD122+Macs respond biochemically and transcriptionally to IL-15 and 2) IL-15-dependent requirements for CD122+Macs in pregnancy in vivo. This proposal will close major gaps in knowledge regarding the mechanism by which IL-15 acts on a novel cellular target to ensure maternal and fetal health during pregnancy.